There is increasing evidence that the release of S100B protein, which is an acknowledged marker of brain injury, is also induced by other causes including hemorrhagic shock. The aim of this study was to investigate the serum concentration of S100B in critically ill mechanically ventilated patients with various degrees of organ dysfunction but without evidence of brain injury or any other neurological disorder and its possible association with tissue perfusion indices. Forty-six critically ill mechanically ventilated patients were studied on intensive care unit admission and until 6 days later. Measurement of serum S100B protein was obtained daily at the time of laboratory sampling and blood gas and lactate analysis. All patients exhibited increased levels of serum S100B levels at least once (median, 0.31 microg/L; interquartile range 25%-75%, 0.17-0.68 microg/L; range 0.04-18 microg/L). There was a significant correlation between S100B and arterial lactate (r, 0.66; P < 0.001), mean arterial pressure (MAP) (r, -0.41; P < 0.001), and pH (r, -0.37; P < 0.001). Serum concentrations of S100B were significantly higher in the presence of hemoglobin (Hb) level of less than 7 mg/dL compared with those measured when Hb level was greater than 7 mg/dL (median, 1.61 mg/dL; interquartile range 25%-75%, 0.66-3.57, vs. median, 0.29; interquartile range 25%-75%, 0.15-0.56, respectively; P < 0.001). Multiple regression analysis with dependent variable S100B and independent variables lactate, Hb, pH, and MAP showed that the only independent variable was the lactate (r, 0.79; r2, 0.62; P < 0.001). Sequential organ failure assessment score was positively associated with S100B values (P < 0.05). In conclusion, serum levels of S100B protein are elevated in critically ill patients, in the absence of an apparent brain damage. Increased S100B values correlated positively with lactate levels and negatively with MAP and pH. Low Hb level is associated with increased S100B levels. These results indicate that serum S100B protein concentration may be related to tissue hypoperfusion.